Skip to main content
SpringerLink
Log in

Aerosol Delivery of Nanoparticles in Uniform Mannitol Carriers Formulated by Ultrasonic Spray Freeze Drying

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

While most examples of nanoparticle therapeutics have involved parenteral or IV administration, pulmonary delivery is an attractive alternative, especially to target and treat local infections and diseases of the lungs. We describe a successful dry powder formulation which is capable of delivering nanoparticles to the lungs with good aerosolization properties, high loadings of nanoparticles, and limited irreversible aggregation.

Methods

Aerosolizable mannitol carrier particles that encapsulate nanoparticles with dense PEG coatings were prepared by a combination of ultrasonic atomization and spray freeze drying. This process was contrasted to particle formation by conventional spray drying.

Results

Spray freeze drying a solution of nanoparticles and mannitol (2 wt% solids) resulted in particles with an average diameter of 21 ± 1.7 μm, regardless of the fraction of nanoparticles loaded (0–50% of total solids). Spray freeze dried (SFD) powders with a 50% nanoparticle loading had a fine particle fraction (FPF) of 60%. After formulation in a mannitol matrix, nanoparticles redispersed in water to < 1 μm with hand agitation and to < 250 nm with the aid of sonication. Powder production by spray drying was less successful, with low powder yields and extensive, irreversible aggregation of nanoparticles evident upon rehydration.

Conclusions

This study reveals the unique advantages of processing by ultrasonic spray freeze drying to produce aerosol dry powders with controlled properties for the delivery of therapeutic nanoparticles to the lungs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

da :

Aerodynamic diameter

DPI:

Dry powder inhaler

EtTP-5:

2,2,10,10-tetraethyl-6,14-bis (triisopropylsilylethynyl)- 1,3,9,11-tetraoxadicyclopenta [b,m] pentacene fluorescent dye

FPF:

Fine particle fraction

LN2:

Liquid nitrogen

NGI:

Next generation impactor

NP:

Nanoparticle

NPAC:

NP aerosol carriers

PLA3.8k-b-PEG5k-OCH3 :

Polylactide-b-poly(ethylene glycol)

PSD:

Particle size distribution

PVA:

Polyvinyl alcohol

SD:

Spray dry

SFD:

Spray freeze dry

THF:

Tetrahydrofuran

References

  1. Weers JG, Bell J, Chan HK, Cipolla D, Dunbar C, Hickey AJ, et al. Pulmonary formulations: what remains to be done? J Aerosol Med Pulm Drug Deliv. 2010;23 Suppl 2:S5–23.

    PubMed  CAS  Google Scholar 

  2. Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, et al. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Env Heal A. 2002;65(20):1531–43.

    Article  CAS  Google Scholar 

  3. Tabata Y, Ikada Y. Phagocytosis of polymer microspheres by macrophages. New Polymer Materials. Berlin: Springer; 1990. p. 107–41.

    Google Scholar 

  4. Wigley FW, Londono JH, Wood SH, Shipp JC, Waldman RH. Insulin across respiratory mucosae by aerosol delivery. Diabetes. 1971;20(8):552–6.

    PubMed  CAS  Google Scholar 

  5. Hinds WC. Aerosol technology, properties, behaviors, and measurement of airborne particles. 2nd ed. New York: John Wiley & Sons, Inc; 1999.

    Google Scholar 

  6. Heyder J, Gebhart J, Rudolf G, Schiller CF, Stahlhofen W. Deposition of particles in the human respiratory-tract in the size range 0.005-15-Mu-M. J Aerosol Sci. 1986;17(5):811–25.

    Article  Google Scholar 

  7. Edwards DA, Hanes J, Caponetti G, Hrkach J, BenJebria A, Eskew ML, et al. Large porous particles for pulmonary drug delivery. Science. 1997;276(5320):1868–71.

    Article  PubMed  CAS  Google Scholar 

  8. Chan HK, Chew NYK. Use of solid corrugated particles to enhance powder aerosol performance. Pharm Res. 2001;18(11):1570–7.

    Article  PubMed  Google Scholar 

  9. Kwok PC, Tunsirikongkon A, Glover W, Chan HK. Formation of protein nano-matrix particles with controlled surface architecture for respiratory drug delivery. Pharm Res. 2011;28(4):788–96. Epub 2010/12/08.

    Article  PubMed  CAS  Google Scholar 

  10. Tsapis N, Bennett D, Jackson B, Weitz DA, Edwards DA. Trojan particles: large porous carriers of nanoparticles for drug delivery. P Natl Acad Sci USA. 2002;99(19):12001–5.

    Article  CAS  Google Scholar 

  11. Broadhead J, Rouan SKE, Rhodes CT. The spray drying of pharmaceuticals. Drug Dev Ind Pharm. 1992;18(11–12):1169–206.

    Article  CAS  Google Scholar 

  12. Vehring R, Foss WR, Lechuga-Ballesteros D. Particle formation in spray drying. J Aerosol Sci. 2007;38(7):728–46.

    Article  CAS  Google Scholar 

  13. Kho K, Cheow WS, Lie RH, Hadinoto K. Aqueous re-dispersibility of spray-dried antibiotic-loaded polycaprolactone nanoparticle aggregates for inhaled anti-biofilm therapy. Powder Technol. 2010;203(3):432–9.

    Article  CAS  Google Scholar 

  14. Maa YF, Nguyen PA, Sweeney T, Shire SJ, Hsu CC. Protein inhalation powders: spray drying vs spray freeze drying. Pharm Res. 1999;16(2):249–54.

    Article  PubMed  CAS  Google Scholar 

  15. Cheow WS, Ng ML, Kho K, Hadinoto K. Spray-freeze-drying production of thermally sensitive polymeric nanoparticle aggregates for inhaled drug delivery: effect of freeze-drying adjuvants. Int J Pharm. 2011;404(1–2):289–300.

    Article  PubMed  CAS  Google Scholar 

  16. Wang Y, Kho K, Cheow WS, Hadinoto K. A comparison between spray drying and spray freeze drying for dry powder inhaler formulation of drug-loaded lipid-polymer hybrid nanoparticles. Int J Pharm. 2012;424(1–2):98–106.

    Article  PubMed  CAS  Google Scholar 

  17. Kho K, Hadinoto K. Optimizing aerosolization efficiency of dry-powder aggregates of thermally-sensitive polymeric nanoparticles produced by spray-freeze-drying. Powder Technol. 2011;214(1):169–76.

    Article  CAS  Google Scholar 

  18. D'Addio SM, Chan JGY, Kwok PCL, Prud'homme RK, Chan HK. Constant size, variable density aerosol particles by ultrasonic spray freeze drying. Int J Pharm. 2012;427(2):185–91.

    Article  PubMed  Google Scholar 

  19. Akbulut M, Ginart P, Gindy ME, Theriault C, Chin KH, Soboyejo W, et al. Generic method of preparing multifunctional fluorescent nanoparticles using flash NanoPrecipitation. Adv Func Mater. 2009;19(5):718–25.

    Article  CAS  Google Scholar 

  20. Ansell SM, Johnstone SA, Tardi PG, Lo L, Xie S, Shu Y, et al. Modulating the therapeutic activity of nanoparticle delivered paclitaxel by manipulating the hydrophobicity of prodrug conjugates. J Med Chem. 2008;51(11):3288–96.

    Article  PubMed  CAS  Google Scholar 

  21. Chen T, D'Addio SM, Kennedy MT, Swietlow A, Kevrekidis IG, Panagiotopoulos AZ, et al. Protected peptide nanoparticles: experiments and brownian dynamics simulations of the energetics of assembly. Nano Lett. 2009;9(6):2218–22.

    Article  PubMed  CAS  Google Scholar 

  22. Chiou H, Chan HK, Heng D, Prud'homme RK, Raper JA. A novel production method for inhalable cyclosporine A powders by confined liquid impinging jet precipitation. J Aerosol Sci. 2008;39(6):500–9.

    Article  CAS  Google Scholar 

  23. Gindy ME, Panagiotopoulos AZ, Prud'homme RK. Composite block copolymer stabilized nanoparticles: simultaneous encapsulation of organic actives and inorganic nanostructures. Langmuir. 2008;24(1):83–90.

    Article  PubMed  CAS  Google Scholar 

  24. Johnson BK, Prud'homme RK. Flash NanoPrecipitation of organic actives and block copolymers using a confined impinging jets mixer. Aust J Chem. 2003;56(10):1021–4.

    Article  CAS  Google Scholar 

  25. Kumar V, Hong SY, Maciag AE, Saavedra JE, Adamson DH, Prud'homme RK, et al. Stabilization of the nitric oxide (NO) prodrugs and anticancer leads, PABA/NO and Double JS-K, through incorporation into PEG-protected nanoparticles. Mol Pharm. 2010;7(1):291–8.

    Article  PubMed  CAS  Google Scholar 

  26. Kumar V, Wang L, Riebe M, Tung HH, Prud'homme RK. Formulation and stability of itraconazole and odanacatib nanoparticles: governing physical parameters. Mol Pharm. 2009;6(4):1118–24.

    Article  PubMed  CAS  Google Scholar 

  27. Liu Y, Tong Z, Prud'homme RK. Stabilized polymeric nanoparticles for controlled and efficient release of bifenthrin. Pest Manag Sci. 2008;64(8):808–12.

    Article  PubMed  CAS  Google Scholar 

  28. Shan JN, Budijono SJ, Hu GH, Yao N, Kang YB, Ju YG, et al. Pegylated Composite Nanoparticles Containing Upconverting Phosphors and meso-Tetraphenyl porphine (TPP) for Photodynamic Therapy. Adv Funct Mater. 2011;21(13):2488–95.

    Article  CAS  Google Scholar 

  29. Shi L, Shan JN, Ju YG, Aikens P, Prud'homme RK. Nanoparticles as delivery vehicles for sunscreen agents. Colloid Surf A. 2012;396:122–9.

    Article  CAS  Google Scholar 

  30. Han J, Zhu Z, Qian H, Wohl AR, Beaman CJ, Hoye TR, et al. A simple confined impingement jets mixer for flash nanoprecipitation. J Pharm Sci. 2012;101(10):4018–23.

    Article  PubMed  CAS  Google Scholar 

  31. Wolak MA, Delcamp J, Landis CA, Lane PA, Anthony J, Kafafi Z. High-performance organic light-emitting diodes based on dioxolane-substituted pentacene derivatives. Adv Func Mater. 2006;16(15):1943–9.

    Article  CAS  Google Scholar 

  32. Chan HK, Chew NYK. Influence of particle size, air flow, and inhaler device on the dispersion of mannitol powders as aerosols. Pharm Res. 1999;16(7):1098–103.

    Article  PubMed  Google Scholar 

  33. Chapter <601>. United States Pharmacopeia 31 - National Formulary 26: United States Pharmacopeial Convention Inc; 2008.

  34. Bronsky EA, Grossman J, Henis MJ, Gallo PP, Yegen U, Della Cioppa G, et al. Inspiratory flow rates and volumes with the Aerolizer dry powder inhaler in asthmatic children and adults. Curr Med Res Opin. 2004;20(2):131–7.

    Article  PubMed  Google Scholar 

  35. Sung JC, Padilla DJ, Garcia-Contreras L, VerBerkmoes JL, Durbin D, Peloquin CA, et al. Formulation and pharmacokinetics of self-assembled rifampicin nanoparticle systems for pulmonary delivery. Pharm Res. 2009;26(8):1847–55.

    Article  PubMed  CAS  Google Scholar 

  36. Sears JT, Huang K, Ray S, Fairbanks HV. Effect of Liquid Properties on Production of Aerosols with Ultrasound. Proceedings, 1977 IEEE Ultrasonics Symposium. 1977:131–3.

  37. Geiser M. Update on macrophage clearance of inhaled micro- and nanoparticles. J Aerosol Med Pulm D. 2010;23(4):207–17.

    Article  CAS  Google Scholar 

  38. Burger A, Henck JO, Hetz S, Rollinger JM, Weissnicht AA, Stottner H. Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol. J Pharm Sci. 2000;89(4):457–68.

    Article  PubMed  CAS  Google Scholar 

  39. D'Addio SM, Saad W, Ansell SM, Squiers JJ, Adamson DH, Herrera-Alonso M, et al. Effects of block copolymer properties on nanocarrier protection from in vivo clearance. J Control Release. 2012;162(1):208–17.

    Article  PubMed  Google Scholar 

  40. Nguyen XC, Herberger JD, Burke PA. Protein powders for encapsulation: a comparison of spray-freeze drying and spray drying of darbepoetin alfa. Pharm Res. 2004;21(3):507–14.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments And Disclosures

This work made use of the Confocal & Electron Microscopy Core Facility at Princeton University and the authors acknowledge Joe Goodhouse for expert help with confocal microscopy. This work was supported through National Science Foundation and the Australian Academy of Science as part of the East Asia and South Pacific Summer Institutes Fellowship (1015344) and through grants from the Australian Research Council (DP0985367 & 120102778).

Author information

Author notes

  1. Philip Chi Lip Kwok

    Present address: Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR

Authors and Affiliations

  1. Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Pharmacy Building A15, Camperdown, New South Wales, 2006, Australia

    Suzanne M. D’Addio, John Gar Yan Chan, Philip Chi Lip Kwok & Hak-Kim Chan

  2. Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, 08854, USA

    Suzanne M. D’Addio, Bryan R. Benson & Robert K. Prud’homme

Authors
  1. Suzanne M. D’Addio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John Gar Yan Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip Chi Lip Kwok
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bryan R. Benson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert K. Prud’homme
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hak-Kim Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Robert K. Prud’homme or Hak-Kim Chan.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 402 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

D’Addio, S.M., Chan, J.G.Y., Kwok, P.C.L. et al. Aerosol Delivery of Nanoparticles in Uniform Mannitol Carriers Formulated by Ultrasonic Spray Freeze Drying. Pharm Res 30, 2891–2901 (2013). https://doi.org/10.1007/s11095-013-1120-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-013-1120-6

KEY WORDS

Search

Navigation